Aryl-alicyclic carboxylic acids and process for their manufacture



Patented Nov. 8, 1949 ARYL-ALICYCLIC CARBOXYLIC ACIDS AND PROCESS FOR THEIR MANUFACTURE Erwin Schwenk, Montclair, N. J.,'and Domenick Papa, Brooklyn, N. Y., assignors to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing. Application November 13, 1948, Ser'ial No. 59,966. In Canada January 30, 1947 9 Claims.

The present invention relates to the manufacture of aryl-alicyclic carboxylic acids, that is, aliphatic carboxylic acids substituted on different carbon atoms by an aryl radicaland an alicyclic radical, the term alicyclic" being employed generically to cover both saturated and unsaturated cycle-aliphatic radicals, including those having internal ring structures, such as the 'hexahydrobenzene, tetrahydrobenzene, tetralyl, terpene and 'terpene-like radicals, and cyclopentane and cyclopentene radicals.

The present application is a continuation in part of our copending application Serial No. 544,831, filed July 13, 944, now abandoned.

We have found that aromatic aldehydes wherein the double bond of the aldehyde group forms part of a conjugated double bond system, as in the case, for example, of benzaldehyde and cinnarnaldehyde, can be condensed with alicyclically substituted aliphatic carboxylic acids, provided that such acids have an oleflnic double bond in activating position with reference to a methylene group in e-position to the carboxyl, such as cycloalkene acetic acid and the cycloallkene-substituted homologous acids, and likewise the corresponding cycloalkylidene acetic and homologous acids, having in the a-pOSltiOl'l. to the carboxylic group either a methylene radical or the group =CH, to form 'dicyclie alkene carboxylic acids, substituted on the 'a-carbon by the cycloalkene radical and on another carbon by the phenyl group.

The condensation reaction of the present invention yields compounds which display a high order of bactericidal efficacy against a wide variety of pathogenic organisms. These compounds are particularly effective against organisms known to cause stubborn infections of the urinary tract. In addition to their bactericidal efliciency, the compounds also have the unexpected, but desirable, propertyof acidifying the urine. Clinical experience has shown that they are effective against urinary tract infections caused by Proteus vulgaris, B. 'm/ocyaneus, L. aerogenes and Strep. fecalis. The clinical efficacy of the-compounds has been particularly outstanding for the treatment of chronic urinary tract infections which have failed to respond to sulfonamide and antibiotic therapy.

The compounds have also shown value in the dysenteria and -S.- alkalescens, the compounds have "been extremely well tolerated and have proved clinically successful. As observed in cases of urinary tract infections, many of the cases of chronic shigellosis have responded to treatment with the compounds of this'invention, Where sulfonamide therapy proved of little value. 01? particularly high eificiency is a(A -cyclohexenyl) p-hydroxyl cinnamic acid.

The products of the present invention are useful also as intermediates for synthetic reactions, such as the production of cyclopentano-polyhydrophenanthrene compounds or the manufacture of iodinated compounds suitable for use as contrast agents'in roentgenographic diagnosis.

According to the present invention, alicyclic carboxylic acids of olefinic character, like A rcycloalkene acetic acid, the isomeric cycloalk-ylidene acetic acid, and the homologous acids,

having a reactive methylene group (or a group convertible thereinto, such as CH=CHCOOH =CHCH2-COOH) in the a-position to the carboxyl group, andeither substituted or unsubstituted in the nucleus, are condensed in accordance with the Perkin reaction, or by various modifications of the Perkin reaction, and preferably although not necessarily in the form of the anhydrous alkali metal, such as potassium salt, or in the form of the free acid and with the aid of a catalyst like a tertiary amine, such as triethyl or tributyl amine, with benzaldehyde, cinnainaldehyde or other aromatic aldehydes wherein the double bond of the aldehyde group forms part of a conjugated double bond system, the nucleusof the aldehyde being substituted or unsubstituted, to form a new class of compounds which may be designated as aryl alicyclic alkene carboxylic acids and their salts. This reaction was quite surprising in view of the vfact that the cycloalkane carboxylic acids do not take part in a Perkin type of reaction. Thus we have heated the anhydrous sodium salt of cyclohexyl acetic acid with benzaldehyde in the presence of acetic anhydride and were able to isolate only cinnamic acid (produced by reaction of the benzaldehyde with acetic anhydride) but not even traces of the'expected cyclohexyl cinnamic acid.

The products may, if desired, be hydrogenated in any suitable manner to produce aryl alicyclic alkane carboxylic acids and their salts.

The starting compounds,.0r only one of them, may contain substituting groups like hydroxyl, ether and ester groups, and halogen groups, preferably iodine. Thus, 3,5-diiodo-4-hydroxy benzaldehyde, 2,4,6-triiodo--hydroxy benzaldehyde, 3,4-diiodo benzaldehyde and the correspondin derivatives of cinnamaldehyde and higher aldehydes may be employed.

The reaction according to the invention is illustrated by the following equations:

I H COOH ELGOOH a COOH The production of intermediates suitable" for the synthesis of cyclopentano polyhydro phenainthrene compounds is shown by the following:

CH O

H B113 0 0H Copper Chromite Quinoline H 0- C O OH HO Iodinated compounds suitable for the manufacture of, or use as, contrast agents for roentgenography may, in accordance with the invention, be prepared in thefollowing manner:

CHO

However, the iodine may be contained in one of the starting compounds as is shown by the following:

o I -I QQWQ H2.COOH

OH on E1 I; I I

l0 OH LOOK Analogous condensation products can be prepared in accordance with the foregoing principles from terpene and terpene-like compounds. The following reactions with menthone are representative of the application of this condensatio procedure to this class of compounds. 1

Menthone can be converted to a carboxyli acid as follows:

For the Reformatsky reaction on menthone. see Wallach and Tholke, Ann. 323, 151 (1902).

Compounds II and III with aromatic aldehydes give compounds of generalformula tz' Q C gCHa A IV a(3-lscpropyl-6-methyln -cyclohexenyl) cinnamic acid substituted or not in the aromaticnucleus.

Ina similar fashion, the compound 3,3,5-trimethyl cyclohexanone can be converted to the corresponding alicyclically substituted cinnamlc acids. r

Compound IV on reduction gives a-(3-isopropyl 6-methy1 cyclohexyl) fl-phenyl propionic acid of the following formula:

{OCH

The corresponding derivatives of the higher unsaturated and (after hydrogenation) saturated aliphatic acids, and of alkadiene carboxylic acids, may be prepared by the use of the appropriate starting compounds, as will be evident to those skilled in the art from the above disclosure;

Where products non-iodinated 'in the phenyl radical but containing a hydroxyl group or a functional derivative thereof, areobtained, the same may be iodinated in known manner, preferably after saturation of the alkene chain, to produce diiodo derivatives suitable for use as" contrast agents.

The following examples illustrate specific procedures inaccordance. with. the. invention.

oi-(A -Gyclohexenyb) cinnamic-acid .A mixture of 17:9 g. anhydrous potassium- Mecycl exenyl acetate .and 110.6 g. :of benzaldehyde was heated for ,8 :hours at 105 :0. with .100 cc. of acetic anhydride. The reaction mixture was then cooled ;.to 60 and :the excess acetic anhydride cautiously decomposed :with water. The reaction mixture was .poured on ice and the semisolid residue extracted with .ether. The acidic fraction was isolated :from the ether by :extraction with sodium carbonate solution. on :acidification of the sodium carbonate extracts the a-(A -cyclohexenyl) cinnamic acid was obtained in the form of a 'pale yellow solid ,melting zat '0-,.152 C. On recrystallization ;from ;a :mixture of acetoneland water the acid-wasobtained inthe formiof long white fine needles, melting at 156 157C,

By the use of the {isomeric anhydrous .potas- I slum cyclohexylidene acetate, this condensation yields 'the same product. It is advisable when usin ,this acid to heat the reaction mixture :for a few additional hours inrorder tosecure a-rcomparable yield.

The MN-cyclohexenyl) cinnamic acidwas reduced as follows: 1 0 s. of Jrthe acid were :dissolved in 200 cc. .of .10%.sodium:hydroxide. The mixture was heated to 90 C. and with -stirringl5 lg. of Raney nickel aluminum alloy :added in the course 'of about one hour. The mixture was stirred .for an additionalrhour at the same temperature, then filtered by decantation from the nickel, and thenickel washed twicewith hot .water. On acidification of the-filtrate and washings to Congo :red paper with concentrated :HCl the crude fi phenyl-u-cyclohexyl propionic acid was obtained in a yield of .10 -g.,;melting,-,at 62-65" .C.

0n recrystallization from a mixture of benzene and petroleum ether :the reduced acid was 0btained as;long fine white needles imelting at 70- EXAMPLE II c-(A C'z clohexenz Z) -p-hydromy cinnamic acid Using either anhydrous potassium-N-cyclo- I hexenyl acetate or anhydrous potassium cyclohexylidene acetate with p-hydroxy vbenzaldehyde under the conditions as .described in .Example I, the a- (A -cyclohexenyl p-hydroxy cinnamic acid is obtained after recrystallization afrom acetone and water as long white needles melting at 19.4-- 195 C.

When ;a- (A -cyclohexenyl) ,p-thydrox cinnamic acid was reduced as described in Example ,I, a quantitative yield of fl-(p-hydroxy phenyD-ccyclohexyl propionic acid was obtained. ,Recrystallized from a mixture of acetone and water .the substituted propionic acid was obtained as fine white needles melting at ISO-181 C.

EXAMPLE'IH a-'(A -'CycZopenten1 Z) p-hydromy cinnamic acid Following the general procedure described ,for Example I, this acid "is obtained by condensing either potassium cyclopentenyl or potassium .cy-

clopentylidene acetate with p-hydrox benzaldehyde. The product is obtained in the form of white needles which melt .at 183 C. with decomposition.

The a-(n -cyclopentenyl') -p-hydr-oxy cinnamic acid when reduced as described in Example I yields the a-cyclopentane-p-(pehydroxy phenyl) propionic acid which melts at 175--l'78 C. Recrystallized from acetone and Water the product was aobtained as white ineedl es 1580-;

a-(u-G-mcthmcy-tA dihydro naphthalene.) 11 M- drozzzy-cinmm'ic acid :Using the general yprocedure described in Example I, 12.8 ;g. .of {anhydrous potassiumefi-methoxy-il-tet-ralidene acetate, 26.1 g. of p hydroxy benzaldehyde and cc-of acetic .anltvdride were heated rtor 10 :to 12 hours .at vJ.05-1.1-.0 C. lllhe condensation product was isolated "by the ether sodium carbonate extraction :method, and after several l-recrystallizations ir-om benzene and ,petroleum .ether.,i-t melted at 189-191 ,C. with rdecomposition.

EXAMPLE V The syntheses as outlined in Examples ,1 to IV can be-modified to avoid the use 'OflEIlBaIIhYHTOUS alkali salts. This modification usesthe free acid, cyclohexenyl, cyclopentenyl, and other ia'licyclic acetic acids with the appropriate aromatic aalde hyde together with suitable :catalysts, :i. 5%, triethyl amine, anhydrous-sodium or :potassium iaee tate, anhydrous potassium carbonate, :et'c.

281g. (.02 ;m.) :ofl-cyclohexenyhacetic 8101152122 15 ('0.2 m.) of benzaldehyde, 20.2;g.r02 ms) Qf'fblliethyl amine and 61.2 is, (10.6 ms) (of acetic anhydride .were heated .for 1042 hours lat 10.0- -C. The reaction mixture was worked lupzas described for Example .1 yielding {am -acyclohexenyl) cinnamic acid, M. 1P. ;156-i'1=5!7 Substitution of the cyclohexenyl :acetic ,acid by cyclohexylidene acetic iac ld. :save a comparable yield, butrequired a few additionalhonrs '01 heating. Substitution of the triethyl "aminejbyzanhydrous potassium acetate :likewise gave ;a ,good yield in the condensation.

,In place -.,of lcyclohexeny'l acetic 'acid {DI-*(If CMCIO- hexylidene acetic acid, and the similarly ;substituted homologous acids. there may rbe employed acetic acid and its ghomologues substituted by cyclo-hexanol, wherein both "the hydroxyl and the acid group ,are ,joined to the same nuclear carbon. During the course --of the reaction 10f such a cyclohexanolacetic acid with an aromatic aldehyde in the presence of acetic anhydride (or other saturated .aliphat-ic acid anhydride) ,.and .ofa catalyst like triethylamine, dehydration .of the cyclohexanol acetic .acid takes place with the formation of either or .both of A ecyclohexenyl acetic acid and cyclohexylidene acetic, acid, .cr homologous acids.

EXAMPLE VI ether extracted with sodium carbonate solutionand the sodium carbonate extract neutralized withdilute hydrochloric acid, treated withrcharcoal and filtered. "The resulting compound was obtained in the 'form of ,a. pale yellow solid melting at 176- 171? .C. The substituted cinnamic acid can be further purified by recrystallization from aqueous alcohol aqueous acetone, or a mixture of benzene and alcohol.

In place of the anhydrous potassium salt .described above, one may use the free acid A i-n'iethyl 'cyclohexenyl acetic acid as outlined in Example V. Condensation can also be effected with l-methyl cyclohexanol-l-acetic acid by using acetic anhydride as a dehydrating and condensing agent. In this type of condensation it is advantageous to use 3 moles of triethylair ine in order to neutralize the acetic acid formed during the dehydration reaction.

3 Other alk yl substituted cycloaliphatic acetic;

acids such as Z-methyl cyclohexenyl acetic acid, 3-methy1 cyclohexenyl acetic acid and the corresponding dimethyl acids may be used. The

preparation of these acetic acids proceeds smoothly by the Reformatsky' reaction, as indicated above for the 3,3,5-trimethylcyclohexenyl acetic acid.

EXAMPLE VII oz- 3,3,5-trimethylcyclohemyl) 3- (ya-hydroxyphenyl) propz'om'c acid 1 Saponification of the above ethyl acetate com-- pound with alcoholic sodium hydroxide yields the 3,3,5-trimethylcyclohexanol-1 acetic acid, which, after recrystallization from petroleum ether, melts at 116-117" C.

When the ethyl acetate derivative described above is dehydrated by any of the usual agents,

for example anhydrous HCl, fused potassium bisulfate, etc., there is obtained the unsaturated compound, ethyl 3,3,5-trimethylcyclohexylidene acetate or the ethyl 3,3,5-trimethyl-A -cyclohexenyl acetate. The type of dehydrating agent used will determine which one of these two isomers is secured. The unsaturated compounds boiled at 76 C./1 mm. When these compounds are saponified with alcoholic sodium hydroxidef there is obtained the 3,3,5-trimethylcyclohexyli'dene acetic'acid or the isomeric A '3,3,5-trimethylcyclohexenyl acetic acid. One of these products which we, have isolated, and which probably is the hexylidene compound, melts at- 80-81 C. after recrystallization from petroleum ether. 1

By condensing 20 gm. of the trimethylcyclohexanol-l acetic acid with 12 gm. of p-hydroxybenzaldehyde in the presence of 150 cc. of acetic anhydride with 40 cc. of triethylamine' as catalyst, there is obtained, after working up the reaction mixture in the normal manner, OL-(AL- 3,3,5 trimethylcyclohexenyl) p hydroxycin- Iiamic acid. Satisfactory yields in this reaction were obtained when the reaction mixture described above was heated for a period of 25-35 hours at 100-110 C. The substituted cinnamic acid, after recrystallization from a mixture ofmethyl alcohol and water, melted at 181-182? C.

The substituted cinnamic acid, when reduced with Raneys alloy and aqueous alkali as mentloned in a previous example, yielded the u-(3,3,5- trimethylcyclohexyl) -c- (p-hydroxyphenyl) propionic acid. This substituted propionic acid, after, recrystallization from aqueous alcohol,

lt d at ts-189.5" 0.. v

8 EXAM-PLE'VIII a- (A -cyclohezcenyl) -p-hydroxycinnami'c acid Ninety-three grams (0.5 in.) of ethylcyclohexanol-l acetate, 61 gm. (0.5 m.) of p-hydroxy-Q benzaldehyde, 150 gm. (1.5 m.) of triethylamin'e and 300 cc. of acetic anhydride were heated,

preferably with stirring, for -35 hours at 100-110 C. At the end of the heating period the reaction mixture was cooled to and the excess acetic anhydride cautiously decomposed by the addition of water. The resulting solution was poured into ice and the product extracted:

with ether. The ether solution was Washed free of acetic acid, the ether evaporated, and the re-- sulting residue, which was principally the ester of the condensation product, was saponified with either aqueous or alcoholic alkali. The saponified solution was then treated with carbon di--' oxide in order to convert the alkali to bicarbonate. After this treatment the solution was heated, treated with charcoal, and filtered. Up on acidification the a-(A -cyclohexenyl) p-hydroxy-;

cinnamic acid was precipitated and filtered. The product obtained melted at 191-l93 C. after recrystallization from a i and water.

In place of the triethylamine, other organic amines may be used for catalyzing the condensation, as well as metallic salts such as sodium and potassium acetate.

a-(Cyclohexyl) p3 (p-hydroxyphenyl) propionic acid was obtained from a-(A -cyclohexs enyD-p-hydroxycinnamic acid by reducing "10 grams of the latter with Raneys alloy and aqueous alkali, as described in the Journal of O'rganic Chemistry, 9,175 (1944). The substituted propionic acid was isolated in the usual man ner and after recrystallization from aqueous ace-j tone melted at ISO-181 C.

The above acids can be converted by the usual reactions into' the corresponding salts; for example, the alkali metal salts, such as sodium" and potassium, the alkaline earth metal salts, such as-those of calcium. and magnesium, etc., as by neutralization in knownmanner with the metal hydroxide or carbonate; and likewise intov the amine salts, like those of mono-, 'di-, and

triethyl amines, dimethylamino ethanol, etc.

As already indicated, and as illustrated by the above examples, the starting compounds may contain substituents like hydroxyl, alkyl', alkoxy and also ester groups, and in 'general'groups which, with the aid of hydrolysis, can bacon: verted into the hydroxy group. The alkyl groups are preferably lower aliphatic-hydrocarbons like methyl and ethyl, while in addition to the meth oxy group also the ethoxy and higher alkoxy groups can be present in place of the hydroxyl" group. -The ester'groups are preferably of the lower aliphaticacids, like the acetate, propionate' and butyrate. Thehydroxyl group and groups convertible into hydroxyl are preferably attached to the benzaldehyde; thus, in addition to the p-hydroxy benzaldehyde specifically disclosed hereinabove, there may be used also methoxy and ethoxy benzaldehyde and likewise .the acetoxy,,

propionoxy and butyroxy compounds which will yield the corresponding condensed compounds in. which the functional substituents can, if desired,

known be converted into the hydroxyl group by methods.

We claim:

1. Process for, themanufacture of dicyclicallyi; substituted aliphatic carboxylic acids. which,

mixture of acetone:

comprises heating and condensing a member of the group consisting of cyclohexanol acetic acid and its salts, wherein the hydroxyl and acetic .acid groups are joined to the same carbon of the cyclohexane ring, with a benzaldehyde under substantially anhydrous conditions and in the presence of the anhydride of a lower fatty acid, whereby initially the cyclohexanol acetic acid is dehydrated to form the corresponding unsatur ated compound, and the latter reacts with the benzaldehyde to produce an alicyclically and aromatically substituted alkene carboxylic acid.

2. Process for the manufacture of dicyclically substituted aliphatic carboxylic acids, which comprises heating and condensing a member of the group consisting of alicyclically substituted acetic acids and their salts, wherein the 1-carbon atom of the alicyclic ring has a double bond connected thereto and wherein the alicyclic ring has from 5 to 6 carbon atoms, with a benzaldehyde under substantially anhydrous conditions and in the presence of the anhydride of a lower fatty acid to produce an alicyciically and aromatically substituted alkene carboxylic acid.

3. Process for the manufacture of dicyclically substituted aliphatic carboxylic acids, which comprises heating and condensing M-cyclohexenyl acetic acid with p-hydroxy benzaldehyde under substantially anhydrous conditions and in the presence of the anhydrlde of a lower fatty acid to produce an alicyciically and aromatically substituted alkene carboxylic acid.

4. Process for the manufacture of dicyclically substituted aliphatic carboxylic acids, which comprises heating and condensing A -cyclohexenyl acetic acid with benzaldehyde under substantially anhydrous conditions and in the presence of the anhydride of a lower fatty acid to produce an alicyclically and aromatically substituted Lalkene carboxylic acid.

- 10 5. A compound of the formula 6. oi-(A -cyclohexenyl) -p-hydroxy cinnamic acid.

7. a-(A -Cyclopentenyl) -p-hydroxy cinnamic acid.

8. a-(A -Alkylcycl0hexeny1) p-hydroxy-cinnamic acid.

9. a-(A -Methylcyclohexenyl) namic acid.

p-hydroxy-cin- ERWIN SCHWENK. DOMENICK PAPA.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,265,184 Miescher et al. Dec. 9, 1941 2,341,016 Brubaker Feb. 8, 1944 2,469,415 Schwenk et a1 May 10, 1949 OTHER REFERENCES Adams et al., Organic Reactions, vol. I pp. 223-228, 240-241 (1942). 

